Inclusion Criteria:
1. Voluntary written informed consent provided.
2. Age ≥ 18 years and ≤ 75 years at enrollment.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0-2.
4. Life expectancy ≥ 6 months.
5. Diagnosis of gastroesophageal junction (GEJ) adenocarcinoma by gastroscopy and histopathology. According to AJCC 8th edition staging, abdominal CT assessment confirms clinical stage cStage III (cT3-4aN1-3M0). For GEJ cancers, only Siewert type III and those Siewert type II cases not requiring combined thoracotomy are eligible.
6. Prior to enrollment, a multidisciplinary assessment involving at least one gastrointestinal surgery attending physician and one radiologist confirms cStage III disease, eligibility for R0 resection with curative intent, patient's agreement to undergo radical surgery, and absence of surgical contraindications as judged by the surgeon.
7. No prior systemic anti-cancer therapy for the current disease, including surgery, radiotherapy, chemotherapy, immunotherapy, etc.
8. Adequate cardiac function to undergo curative-intent resection. Patients with underlying ischemic, valvular, or other significant heart disease should undergo preoperative evaluation by a cardiologist if clinically indicated.
9. Adequate organ function, meeting the following laboratory parameters (without supportive measures within specified timeframes):
* Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L (without granulocyte colony-stimulating factor support within 14 days).
* Platelets ≥100 × 10⁹/L (without transfusion within 14 days).
* Hemoglobin \>8 g/dL (without transfusion or erythropoietin use within 14 days).
* Total bilirubin ≤1.5 × upper limit of normal (ULN); OR total bilirubin \>1.5 × ULN but direct bilirubin ≤ ULN.
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN.
* Serum creatinine ≤1.5 × ULN AND calculated creatinine clearance (Cockcroft-Gault formula) ≥60 mL/min.
* Adequate coagulation, defined as International Normalized Ratio (INR) or prothrombin time (PT) ≤1.5 × ULN.
* Normal thyroid function, defined as thyroid-stimulating hormone (TSH) within normal range. If baseline TSH is outside normal range, subjects with total T3 (or FT3) and FT4 within normal range are eligible.
* Myocardial enzymes within normal limits (subjects with isolated lab abnormalities judged by the investigator as clinically insignificant may be eligible).
10. For female patients:
* Postmenopausal (defined as ≥1 year of amenorrhea without an alternative cause), OR surgically sterilized (removal of ovaries and/or uterus), OR, if of childbearing potential, must meet all the following:
* Negative pregnancy test within 7 days prior to first dose.
* Agreement to use highly effective contraception (annual failure rate \<1%) or practice abstinence from heterosexual intercourse from signing informed consent until at least 120 days after last dose of investigational product and at least 9 months after surgery. Highly effective methods include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
* Must not be breastfeeding.
11. For male patients: Agreement to practice abstinence from heterosexual intercourse or use contraception with the following details: If partner is a woman of childbearing potential or is pregnant, the male patient must remain abstinent or use a condom from signing informed consent until at least 120 days after last dose of investigational product and at least 9 months after surgery. The reliability of sexual abstinence should be evaluated considering the study duration and the patient's preferences and lifestyle. Periodic abstinence (calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods.
12. The subject has read and fully understands the patient information, and has signed the informed consent form.
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1. History of other malignancies within the past 5 years or concurrent malignancy. Exceptions include cured localized tumors such as basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, carcinoma in situ of the prostate, cervical carcinoma in situ, breast carcinoma in situ, Stage I lung cancer, Stage I colorectal cancer, etc.
2. Planned or prior organ or bone marrow transplantation.
3. Blood transfusion within 2 weeks prior to the first dose, history of bleeding, or any grade 3 or higher bleeding event (per CTCAE v5.0) within 4 weeks prior to screening.
4. Coagulation disorders or bleeding tendency (INR \>1.5 times the upper limit of normal \[ULN\] without anticoagulant use). Patients receiving therapeutic anticoagulation with agents such as warfarin, heparin, or analogues. Prophylactic use of low-dose warfarin (1 mg orally, once daily) or low-dose aspirin (≤100 mg daily) is permitted if INR ≤1.5.
5. Arterial or venous thromboembolic events within 6 months prior to screening, such as cerebrovascular accident (including transient ischemic attack), deep vein thrombosis (except catheter-related thrombosis secondary to prior chemotherapy deemed resolved by the investigator), and pulmonary embolism.
6. Myocardial infarction within 6 months prior to the first dose, or poorly controlled arrhythmias (including QTc interval ≥450 ms for males or ≥470 ms for females, calculated using Fridericia's formula).
7. Cardiac insufficiency meeting NYHA Class III-IV criteria, or left ventricular ejection fraction (LVEF) \<50% as measured by echocardiogram.
8. Urinalysis showing protein ≥++ and confirmed 24-hour urine protein quantification \>1.0 g.
9. Clinically symptomatic pleural effusion or ascites requiring intervention.
10. Known human immunodeficiency virus (HIV) infection.
11. Active pulmonary tuberculosis.
12. Non-healing wounds or incompletely healed fractures.
13. History or current presence of interstitial lung disease, pneumoconiosis, radiation pneumonitis, drug-related pneumonia, severely impaired pulmonary function, or other conditions that may interfere with the detection or management of suspected drug-related pulmonary toxicity.
14. Known active or suspected autoimmune disease. Patients in a stable state of the disease at enrollment (not requiring systemic immunosuppressive therapy) are allowed.
15. History of severe chronic autoimmune diseases (e.g., systemic lupus erythematosus), inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease), chronic diarrheal diseases (e.g., irritable bowel syndrome), sarcoidosis, or tuberculosis. Patients with active hepatitis B, hepatitis C, or HIV infection are excluded. Non-severe, well-controlled immune disorders (e.g., dermatitis, arthritis, psoriasis) are allowed. Hepatitis B virus titer \<500 copies/mL is allowed.
16. Requirement for systemic corticosteroid therapy (\>10 mg/day prednisone equivalent) or other immunosuppressive medications within 14 days prior to the first dose or during the study. Topical, inhaled, or physiologic replacement steroid doses (≤10 mg/day prednisone equivalent) are permitted in the absence of active autoimmune disease.
17. Any active infection requiring systemic anti-infective therapy within 14 days prior to the first dose. Prophylactic antibiotic use (e.g., for urinary tract infection or COPD) is allowed.
18. Administration of live vaccines within 28 days prior to the first dose. Inactivated seasonal influenza vaccines are allowed.
19. Prior treatment with antibodies/drugs targeting immune checkpoints (e.g., PD-1, PD-L1, CTLA-4 inhibitors).
20. Concurrent participation in another interventional clinical trial. Participation in observational or surgical studies is allowed.
21. Known history of allergy or intolerance to any component of the investigational product(s).
22. History of alcohol abuse, drug abuse, or substance dependence. Patients who have ceased alcohol consumption are allowed.
23. Patients considered likely to be non-compliant with the study protocol, affecting efficacy or safety assessments, or those with incomplete data.
24. Pregnant or breastfeeding women.
25. Any condition affecting gastrointestinal absorption (e.g., dysphagia, prior gastrectomy, uncontrolled vomiting), ongoing tube feeding or parenteral nutrition, anorexia nervosa, anorexia due to psychiatric disorders, or inability to eat due to pain.
26. Current or planned use of other appetite-stimulating or weight-gaining medications (e.g., corticosteroids \[except short-term dexamethasone during chemotherapy\], androgens, progestins, thalidomide, olanzapine, anamorelin, or other appetite stimulants).
27. Cushing's syndrome, adrenal or pituitary insufficiency; poorly controlled diabetes mellitus.
28. Postmenopausal women with a history of abnormal vaginal bleeding within the past year; premenopausal women with a history of abnormal endometrial thickening (\>15 mm) within the past year.
29. Any arterial thromboembolic event within 6 months prior to the first dose; Grade 3 or higher venous thromboembolic event per NCI CTCAE v5.0 requiring urgent intervention (e.g., pulmonary embolism, cardiac chamber embolism); transient ischemic attack, cerebrovascular accident, hypertensive crisis, or hypertensive encephalopathy; acute exacerbation of chronic obstructive pulmonary disease within 1 month prior to the first dose; uncontrolled hypertension (SBP ≥160 mmHg or DBP ≥100 mmHg despite oral antihypertensive medication).
30. History of severe bleeding tendency or coagulation dysfunction; clinically significant bleeding symptoms within 1 month prior to the first dose, including but not limited to gastrointestinal bleeding, hemoptysis (defined as coughing or spitting ≥1 teaspoon of fresh blood or small blood clots, or coughing blood without sputum; blood-tinged sputum is allowed), epistaxis (excluding minor nosebleeds and blood-tinged postnasal drip).
31. Any condition that may increase the risk associated with study participation or investigational product use, or other severe, acute, or chronic medical conditions that, in the investigator's judgment, make the patient unsuitable for the clinical study.
32. Any other circumstances deemed by the investigator to make the patient unsuitable for participation in this clinical trial.
